Clopidogrel and its hydrogen sulfate salt being chiral compounds, their S(+)enantiomer is a commercially significant drug reported to selectively interfere with Adenosine-Di-Phosphate (ADP) mediated platelet aggregation and cause an irreversible non-competitive inhibitor of platelet function with excellent anti-thrombotic activity. The dextrorotatory enantiomer bearing the international non-proprietary name (INN) Clopidogrel and its pharmaceutically acceptable salts have been disclosed in U.S. Pat. Nos. 4,847,265, 5,132,435, EP: 0281459, EP: 465358.
S(+)Clopidogrel hydrogen sulfate [may also be referred as S(+)Clopidogrel bisulfate has appeared in US Pharmacopoeia [USP]. According to USP monograph 27NF22, IInd Supplement, effective from 1, Aug. 2004, the minimum requirement of desired chiral purity of S(+)enantiomer is 99.0% by HPLC.
Generally the enantioselective-enriched compound can be prepared in two different ways. One is starting with enantioselective material and two is starting with racemic mixture following the resolution either at the intermediate stage or at the final stage.
The preparation from enantioselective-enriched compound is more preferred because it not only enhances yield of enantioselective-enriched end product, but also eliminates chances of impurity.
The preparation from racemic mixture to a racemic mixture of the end product followed by resolution to get enantioselective-enriched end product involves an additional step of resolution of racemic mixture of end product which in-turn reduces the yield of the desired end product. An attempt has been made to overcome the problem of yield by recycling the undesired intermediate after racemization, but these steps have been observed to increases the cost of production [WO2004/108665]. Further, it has been observed that the overall yield is not encouraging.
The preparation from racemic mixture to an enantioselective-enriched end product via resolution at the intermediate stage suffers from the problem of difficulty in isolation of the intermediate. In case the intermediate is resolved in-situ, then the yield of the process is quite low [U.S. Pat. No. 5,204,469].
Accordingly, the resolution techniques are associated with following limitations:                1. requirement of suitable resolving agents considered as chiral auxiliary;        2. recycling of resolving agents; and        3. isolation and racemization of undesired enantiomers.        
Therefore, the preparation of the enantioselective-enriched compound is preferred from the enetioselective-enriched starting compound.
The U.S. Pat. No. 4,529,596 disclosed various derivatives of clopidogrel of Formula-I and their method of preparation. However, this patent disclosed the clopidogrel as racemic mixture of its enantiomers and no method of resolution has been disclosed. As per the processes of this patent esters of Formula I could be prepared by condensation of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine with an alpha-chlorophenyl acetate and amides of Formula I could be prepared by reacting an acid of formula (I)(R═OH) either with amine of formula R1—NH—R2 or with the alcohol of formula R—OH. In this patent, for the economic reasons, the reaction of acid of formula (I)(R═OH) with alcohol of formula R—OH was preferred as compared to other two alternatives. This method could also be employed for synthesis of certain higher esters of Formula I. The other two alternatives were held to be more uneconomical as compared to the reaction of acid of formula (I)(R═OH) with alcohol of formula R—OH. The preferred process has significant drawbacks when practiced on an industrial scale. For example, the alpha-halo-acetic acid derivatives used in the process are lachrymators and irritants and, therefore difficult in handling.
U.S. Pat. No. 4,847,265 discloses a method of resolution of racemic mixture of clopidogrel by forming a salt of the racemic mixture of clopidogrel with an optically active acid, preferably levo-rotatory camphor-10-sulfonic acid in an inert solvent. The main problem with this method is that the resolving agent employed, that is levo-rotatory camphor-10-sulphonic acid is expensive which enhances cost of production of enantiomeric clopidogrel. Another problem of this method is that the end product is prepared in very poor yield of about 50% due to formation of undesired levo-rotatory isomer of clopidogrel. Therefore, the attempt is to avoid the resolution of clopidogrel free base to get the desired end product —S(+)clopidogrel hydrogen sulfate.
U.S. Pat. No. 5,204,469 discloses that the clopidogrel of Formula-I can also be prepared by reacting methyl alpha-(2-thienylethylamino)(2-chlorophenyl)acetate, a compound of Formula-II with a formylating agent in presence of a solvent and then followed by cyclisation of the intermediate compound formed in the presence of an acid under anhydrous condition. The intermediate compound optionally could be isolated and then cyclised in the presence of an acid.

The major problem of this process is that either it is a two step process requiring a step of formylation and then followed by a step of cyclisation or a three step process requiring a step of formylation, a step of isolation of intermediate and then followed by a step of cyclisation of the intermediate which has not been confirmed in this patent.
Further problem of this method is that whether a racemic mixture of compound of Formula II or a stereospecific compound of Formula II is taken as a starting material, the clopidogrel free base is isolated from the aqueous layer at a pH above 7 that is at an alkaline pH which is achieved by addition of sodium bicarbonate. It has been observed that when the clopidogrel free base is separated out at a basic pH, that is at a pH above 7, then it is obtained along with various chemical impurities which are very difficult to be separated out. Hence, this process cannot result in higher yield of clopidogrel free base of higher purity. The purity of clopidogrel free base may be increased, but by additional steps of repeated purification/recycling thereby making the process highly uneconomical.
Another problem of this process is that it requires anhydrous conditions to be maintained.
Still further problem of this process is that it requires additional organic solvents such as methylene chloride to dissolve dextrorotatory compound of Formula-II and anhydrous dimethylformamide containing hydrochloric acid for cyclisation of the intermediate prepared thereby resulting in further increase of cost of the process for preparation of dextrorotatory clopidogrel free base.
The S(+)clopidogrel hydrogen sulfate prepared by known methods is observed to have optical rotation of about 53 degree with chiral purity of less than about 98% as measured by HPLC. The requirement is to have S(+)clopidogrel hydrogen sulfate having optical rotation of about 55.0 degree or more with chiral purity of about 99.0% or more. The prior art does not teach how to enhance the optical rotation of S(+)clopidogrel hydrogen sulfate to have higher chiral purity, which is relatively more suitable as per US pharmacopeal requirement.
The another problem for preparing S(+)clopidogrel hydrogen sulfate having higher efficacy due to higher optical rotation with higher chiral purity from S(+)clopidogrel free base is that on reaction with conc. sulfuric acid, it results in formation of undesired clopidogrel hydrogen sulfate and other chemical impurities thereby does not result in preparation of S(+)clopidogrel hydrogen sulfate having desired optical rotation and chiral purity.
The another problem observed during purification of S(+)clopidogrel hydrogen sulfate having lower efficacy due to lower optical rotation and lower chiral purity to have S(+)clopidogrel hydrogen sulfate having higher efficacy due to higher optical rotation with higher chiral purity is that the undesired clopidogrel hydrogen sulfate [racemic and/or levo-rotatory] and other impurities also precipitate out along with desired S(+)clopidogrel hydrogen sulfate and further purification of such mass is very difficult to obtain desired S(+)clopidogrel hydrogen sulfate.